Preservation of personal care products from microbial contamination has become a difficult task since the available approved antimicrobials are very few and those which have good antimicrobial activity are quite toxic. Consumers want products meant for topical applications to be free from toxic antimicrobials that are used as preservatives. This situation is partly addressed by exploiting the synergy between disparate of antimicrobials. It allows one to achieve not only the broad spectrum of activity against the variety of microbes but high level of antimicrobial efficacy is achieved despite reducing the concentration of individual antimicrobial. Commercially, such synergistic blends are available where antifungal chemicals are combined with antibacterial chemicals.
Currently, a number of blends are available for preservation of personal care products where synergy between antimicrobials is exploited in lowering the concentration of individual ingredient and another great advantage is that the microbes cannot develop resistance very easily if they are attacked by a combination of antimicrobials.
The following are the leading manufacturers of antimicrobials that offer synergistic blends to tackle the preservation of personal care products. BASF/Cognis (Germany), Thor (England), Schulke and Mayr (Germany), International Specialty Products (ISP, USA), Rohm and Haas (USA), Lonza (Germany/Switzerland), Arch Personal Care Products (USA), Nalco (USA) Rhodia-McIntyre (France-USA), Clamant (Germany), Induchem (Switzerland), and Symrise (USA), Sharon Laboratories (Israel) and Galaxy Surfactants Ltd (India).
The most effective antimicrobials that are used for creating these combinations for topical personal care products can be classified into four major categories. The four categories are 1) phenolic antimicrobials 2) formaldehyde releasing compounds 3) quaternary ammonium compounds and 4) halogenated antimicrobials. The examples of phenolic compounds are parabens and the examples of phenolic halogenated compounds are, Triclosan and chloroxylenol. Chloroxylenol is significantly toxic to mammals and is a skin irritant with quite allergic properties. The examples of nonphenolic halogenated compounds are 2-bromo-2-nitro-1, 3 propane diol, and chloroisothiazolinone. The examples of formaldehyde releasing compounds are DMDM hydantoin, diimidazolidinyl urea and examples of quaternary ammonium compounds are benzethonium chloride and cetyl pyridinium chloride.
Parabens:
Parabens are esters of p-hydroxy benzoic acid. Some parabens are active against bacteria and some show activity against fungi. Usually they are used in combination of at least two or in most cases combination of 4 to 5. In fact all five (methyl, ethyl, propyl, butyl and isobutyl) parabens are often times combined with other antimicrobial to seek lower dosage and synergy in the antimicrobial efficacy. For example, Clariant's ‘Phenonip’ is a blend of six antimicrobials out of which the five are parabens. The same company offers blends of only parabens as ‘Nipastat’ and ‘Nipasept’, Cognis's Elestab FL 15, Elestab 48, Elestab 50J, Elestab 305, Elestab 388, Elestab 3344, Elestab 4112, Elestab 4121, Elestab 4150 Lipo are all blends of antimicrobials with at least one paraben in them. Induchem's Uniphen P23, ISP's Germaben and LiquaPar series of blends contain several parabens. Galaxy Surfactants offers Galguard NK1 and Galguard NK2 blends that are based on four and five paraben blends respectively with phenoxy ethanol. Five blends by McIntyre/Rhodia from their ‘Paragon’ series have several parabens. Neolone MXP of Rohm and Haas has parabens with methyl isothiazolinone. Neo-Dragocide series of blends from Symrise has parabens. Euxyl K 300 of Schulke and Mayr has five parabens. Thor's Microcare PM4 and Microcare PM5 have four and five parabens respectively. What it shows is that the parabens are doing a great job of being good preservatives.
All phenolic antimicrobials have phenolic ‘hydroxyl’ group and that is a very reactive organic functionality with very acidic hydrogen with pKa of 10. Parabens are phenol derivatives and the other compounds as mentioned above are widely used. However, during 1998 to 2004 a few scientific publications implicated parabens in endocrine disrupting estrogenic activity and some other deleterious effects on reproductive systems in various test methods. [(Pedersen, K. L. et al., The preservatives ethyl-, propyl-and butylparaben are estrogenic in an in-vivo fish assay, Pharmacology & Toxicology (Vol. 86(3), pp 110-13, March 2000); Routledge, E. J., et al., Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic, Toxicology and Applied Pharmacology (Vol. 153(1), pp. 12-19 (November 1998); and Kang, K. S. et al, Decreased sperm number and motile activity on the F 1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben), Journal of Veterinary Medical Science (Vol. 64(3), pp. 227-35 (March 2002); and Philippa Darbre and Philip Harvey, Endocrine disrupters and human health: could estrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women, Journal of Applied Toxicology, 24 (3): 167-176, (2004)].
In view of these scientific publications, in 2005 Cosmetic Directive of EU reexamined the severity and fixed the maximum usage levels of parabens for topical applications. However, this clean chit does not seem to be adequate to mitigate the grave concern about the usage of parabens as preservatives. The stigma on paraben continues and personal care industry is asking for preservatives that are free of parabens.
Formaldehyde Releasing Antimicrobials:
Formaldehyde is classified as Category 3 CMR (carcinogenic, mutagenic and reproductive toxicity). However, it is interesting to note that a few antimicrobials that slowly release formaldehyde are still being used and being commercially manufactured. Due to the paucity of effective and well-accepted antimicrobials, the industry is forced to continue with the using formaldehyde donors like DMDM hydantoin, imidazolidinyl urea, and diazolidinyl urea. The formaldehyde released by these substances is capable of reacting with several cosmetic ingredients via its very reactive aldehydic carbonyl functionality. For example, the only available and globally approved UV-A absorber, Avobenzone, reacts with formaldehyde that is released by formaldehyde derivatives. This is a big disadvantage for sunscreen formulations. Preservative blends, Clariant's Niapaguard PDU and Cognis's Elestab 305, ISP's Germaben II, Germaben H-E, exploit combinations of parabens with diazolidinyl urea. ISP's Germall Plus and Lonza's Glydant Plus have diazolidinyl urea along with iodopropynyl butyl carbamate (IPBC) in them. McIntyre's Paragon series has DMDM hydantoin and other antimicrobials like paraben, phenoxy ethanol and IPBC. Symrise's Neo-Dragocide and Thor's Microcare IMP exploit synergy between parabens and imidazolidinyl urea.
Quaternary Ammonium Antimicrobials:
The third category of the quaternary ammonium compounds (examples are cetyl pyridinium chloride, benzethonium chloride, benzalkonium chloride, polyaminopropyl biguanide), has been of limited use for personal care industry due to specific incompatibilities with other cosmetic ingredients.
Lonza's Geogard series of preservative blends avoids use of parabens in their new creations (Geogard 233S, Geogard 233S, Geogard 233S, Geogard 361) however, these antimicrobial compositions are based on cationic benzethonium chloride which gets deactivated by many anionic ingredients that form important part of topical personal care formulations.
Halogentated Antimicrobials:
Nalco's Merguard series (four blends) banks on halogenated molecules, methyl dirbromo glutaronitrile and 2-bromo-2-nitro-1,3-diol. Several blends of Euxyl series from Schulke and Mayr are based on chlorothiazolinones, methyl dibromo glutaronitrile, 2-bromo-2-nitro-1,3-diol and diazolidinyl urea. Microcare series from Thor employs parabens, 2-bromo-2-nitro-1,3-diol, iodopropynyl butylcarbamate (IPBC), imidazolidynyl urea, and diazolidinyl urea.
The other examples of halogenated antimicrobials are chlorphenesin, and chlorhexidine. It is common knowledge that like phenolic compounds, the halogenated organic molecules exhibit significant levels of toxic effects. For example, IPBC has risk of thyroid hormonal disturbances due to its iodine content. It has not been allowed in Japan and in EU it is allowed only up to 0.02% in leave-on products. Similarly EU permits usage of methyl dirbromo glutaronitrile only up to 0.1% and that too in only rinse-off products. Bronopol, 2-bromo-2-nitropropane-1,3-diol, is implicated in generation of carcinogenic nitrosoamines on interacting with some of the nitrogen containing cosmetic ingredients. Methyl chloro isothiazolinone is so powerful antimicrobial that it is allowed only in rinse-off products at 15 ppm concentration. Chloromethyl isothiazolinone does have a very broad spectrum of anti-microbial activity. But the toxicity of such powerful anti-microbials is extremely high and hence cosmetic formulators do not prefer to use this kind of powerful antimicrobial in the cosmetics that remain on human skin for a long time. It is reasonable to expect that any thing that is strong bactericidal at a low concentration (ppm level) is likely to be equally lethal to any other cells of a living organism, including human cells. This is the precise reason why in Japan chloromethyl isothiazolinone is not allowed for preservation if the product is going to come in contact with the mucous membrane.
In spite of these serious concerns associated with the four major categories of antimicrobials that are used as preservatives, the cosmetic formulators have no choice but to continue using whatever is available. The manufacturers have been selling the blends of 2 to 5 antimicrobials in order to increase the efficacy through the synergy. However, almost all effective antimicrobial blends offered by the leading world manufacturers either contain a paraben or a formaldehyde donor or a halogenated molecule (‘Preservatives for Cosmetics’ by David Steinberg, Allured Publishing Corporation, 2nd Ed, 2006).
The consumer concern about parabens and formaldehyde releasing antimicrobials and the industry's continuous search for a new safe antimicrobial as well as new blends and combinations to address the current needs have been nicely covered in a ‘Preservative Update’ by Tom Branna, in Household and Personal Products Industry (HAPPI), May issue (2006). So far there is very little success with the search of a new safe ideal molecule and all the major manufacturers of antimicrobial preservatives for cosmetics continue to manufacture and sell preservative blends with either parabens or with formaldehyde donors. As mentioned in the foregoing discussion on the blends, commercial synergistic blend with trade name of ‘Phenonip’ by Clamant is nothing but parabens with phenoxy ethanol. Similarly, ‘Germaben II’ of ISP is a commercial blend of diazolidinyl urea with parabens, Lonza's ‘Glydant Plus’ has DMDM hydantoin. McIntyre's Paragon PPM has all five parabens with phenoxy ethanol, so does Microcare PM-5 by Thor. Euxyl K300 by Schulke and Mayr, Galguard NK1 & 2 from Galaxy Surfactants as well as Neolone MXP from Rohm and Haas too has parabens with phenoxy ethanol.
Preserving personal care products from microbial degradation is quite challenging. Most topical cosmetics and dermatological products, in the form of creams, lotions, gels, shampoos, body washes, face washes contain significant amount of water in them that provides a very hospitable environment for the microbial growth. In addition to water, the other cosmetic ingredients can also be a good source of nutrients to microbes. Another pertinent point to be reckoned here is that the shelf-life of the personal care products and the period after opening the container by the consumer is quite long compared to pharmaceutical products or food products. Unlike pharmaceuticals, cosmetics products are neither sterilized and nor packed in hermetic conditions. Thus, the requirement for the preservation of the personal care products is indeed quite challenging. This is further compounded by the limited choice of antimicrobials. Most antimicrobials available today for preservation of personal care products are not the ideal ones. The consumer's awareness is very high and expects the preservatives in personal care products to be not only effective but extremely mild on the person since one uses personal care products life long. In recent years, a host of non-government organizations (NGOs) have targeted parabens and other preservative systems that include formaldehyde donors, halogenated organic molecules and phenolic compounds. Bad press (suspected endocrine disrupting activity) for the parabens forced antimicrobial manufacturers and the cosmetic industry to search for the alternatives to paraben.
The manufacturers of preservatives and personal care industry are looking for better and safer alternatives. Though discovering a new powerful and toxicologically safe broad spectrum antimicrobial is possible, it is a long and expensive process to discover new material and have it approved by the Cosmetics Directives and accepted by the global markets. According to the experts in industry an ‘ideal preservative’ is like “Holy Grail” and the industry has stopped looking for the ‘ideal’ preservative. (Donald Orth in ‘Insights into cosmetic microbiology’, Allured Publications, 2010).
Thus, faced with a consumer rebellion against certain categories of preservatives, much of the current effort by the industry has been directed in discovering synergy between mixtures of existing preservatives and in finding personal care ingredients that may have a coincidental antimicrobial activity (John Woodruff, Soap Perfumery and Cosmetics, September, 2006).
Recently Arch Personal Care, USA, invented MicroKill COS and MicroKill PCC that are based on chlorphenesin and chloroxylenol respectively. It is to be noted that these preservatives are free from parabens and free from formaldehyde releasers but they are halogenated molecules. Lonza's recent commercial introductions commercial are Geogard 2333, Geogard 2355, and Geogard 361 are based on benzethonium chloride, a quaternary ammonium compound. ISP's latest invention is Liquagard which is nothing but iodopropynyl butyl carbamate (IPBC), again a halogenated molecule. Vertellus Specialities, Italy, launched ZeStat that is again a quaternary ammonium surfactant, cetyl pyridinium chloride.
In order to get rid of formaldehyde donors and halogenated molecules International Specialty Products, USA, came up with ‘Octiphen’ which is a combination of phenoxy ethanol and caprylyl glycol. Schulke and Mayr, Germany, launched the preservative blends Euxyl K600, K700 and K702 that are free of formaldehyde donors, parabens and halogenated compounds. These are based on combinations of organic acids like dehydroacetic acid, benzoic acid and formic acid.
Octiphen BSB-N from ISP is a combination of benzoic acid, sorbic acid and benzyl alcohol. Similarly Sharon MX 705 is a blend of sorbic acid, benzyl alcohol, benzoic acid and dehydroacetic acid.
In summary, the antimicrobial manufacturers do not seem to be looking to invent the ‘ideal’ preservative but synergistic combinations of antimicrobials to avoid parabens or formaldehyde donors. However, in most cases one can see quaternary compounds or halogenated molecules form the important constituents of the antimicrobial blends where parabens and formaldehyde donors have been omitted. In other cases the combination of organic acids are being used. A limitation of low molecular weight organic acids is that they are effective in acid form and hence only at low pH show efficacy as antimicrobial preservative. For example, benzoic acid is effective if it remains as benzoic acid and loses it efficacy in its ‘benzoate’ form.
There have been some attempts to create synergistic blends avoiding parabens and formaldehyde donors have been reported. For instance, in 2008, Ellen Rozsa et al. reported a synergistic preservative system having an oil-miscible glycol and an enzymatic composition (U.S. Pat. No. 226,568, 2008). The synergistic preservative system of this patent application demonstrates enhanced anti-fungal, anti-bacterial, and anti-microbial efficacy and is free of formaldehyde donors, parabens, and isothiazolinones. However, again, using enzymatic compositions as preservative for personal care product may not be globally accepted since the enzymes used are glucose oxidase and lactoperoxidase.
Although several undecylenic acid derivatives have been reported to possess some antifungal activity, these have not been exploited commercially for the preservation of personal care formulations. For example, undecylenoyl glycine is reported to possess anti-acne activity, (CAS No 54301-26-7, EINECS No 427-430-5) when used along with other ingredients like zinc gluconate, capryloyl glycine, plant extracts from rathania, tea, cinnamon, willows or hamemelis (EP 0983055131). However, the significant limitation of using lipidated amino acid like undecylenoyl glycine is that they show effectiveness only when present in carboxylic acid form. When pH is more than 7 then part of it goes in the salt form (carboxylate form) and it loses its efficacy. This is a severe limitation that pH of the cosmetic formulation has to be on the acidic side (WO 99/27902/EP 0983055B1).
Interestingly, in 2004 use of combination of Wasabi extract along with undecylenoyl glycine (lipidated amino acid) as a co-preservative for protection of personal care preparations was reported by D. Misner (US 2004096528A1). This is the sole instance from the prior art that suggests use synergistic combination of undecylenoyl derivatives with other ingredients for the purpose of preservation.
The present invention overcomes this limitation by creating preservative systems that have antimicrobial undecylenoyl derivative that remains active over a broad pH range.
In summary, personal care industry has limited choice of anti-microbial agents that can be safely used for preservation of formulations that are accepted by the end consumers. The personal care industry is looking for an absolutely non-toxic, safe and broad spectrum anti-microbial that would be acceptable by the consumers all over the world. Other important and essential criterion is that the preservative system made up of either a single antimicrobial substance or a blend should be completely compatible with commonly used cosmetic ingredients. These requirements are not easily addressed by designing a new antimicrobial molecule because it takes at least a decade before a globally accepted molecule is born.
In view of the absence of an ‘ideal’ antimicrobial and the current unavailability of safe, effective and non-controversial preservation systems, there is an urgent need to meet this requirement from ‘synergistic’ combination of established personal care ingredients that are ‘very safe and mild’ and that would give broad range of protection (effective against Gram positive and Gram negative bacteria, yeast and mould) and be free of formaldehyde donors, free of halogenated molecules and phenolic molecules and quaternary ammonium compounds and that would be acceptable to the global community. Thus, despite the growing concerns, the personal care industry is forced to use parabens, formaldehyde donors and halogenated compounds. This is simply because there is no effective and efficacious alternative preservative system available that would replace them. Preservative industry's efforts in this direction have been met with little or no success at all.
Hence there was a need to provide an efficient preservation system comprising synergistic combination of preservatives for personal care formulations.
The present invention thus provides a preservative combination made up of very ‘safe and nontoxic’ personal care ingredients and that are free from parabens, formaldehyde donors, phenolic compounds, halogenated molecules and quaternary ammonium molecules.